[9,10-dimethoxy-3-(2-methylpropyl)-1h,2h,3h,4h,6h,7h,11bh-pyrido-[2,1-a]isoquinolin-2-yl]methanol and compounds, compositions and methods relating thereto

ABSTRACT

Compounds having a structure of formula (I), including stereoisomers and pharmaceutically acceptable salts and solvates thereof: 
     
       
         
         
             
             
         
       
     
     wherein R 1  is as defined herein. Such compounds are inhibitors of the vesicular monoamine transporter 2 (VMAT2) and have utility for treating, for example, hyperkinetic disorders. Also disclosed are compositions containing these compounds in combination with a pharmaceutically acceptable carrier or diluent, as well as methods relating to the use in a subject in need thereof.

BACKGROUND Technical Field

This disclosure relates generally to[9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanoland compounds, compositions and methods related thereto.

Description of the Related Art

Dysregulation of dopaminergic systems is integral to several centralnervous system (CNS) disorders, including hyperkinetic movementdisorders and conditions such as schizophrenia and bipolar disease. Thetransporter protein vesicular monoamine transporter-2 (VMAT2) plays animportant role in presynaptic dopamine release and regulates monoamineuptake from the cytoplasm to the synaptic vesicle for storage andrelease.

3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]-isoquinolin-2-one,also known as tetrabenazine (TBZ), has been used as a drug for decades.Tetrabenazine is a potent, reversible inhibitor of catecholamine uptakeby vesicular monoamine transporter-2 (VMAT2) (IC₅₀=3.2 nM) (see, e.g.,Scherman et al., Proc. Natl. Acad. Sci. USA, (1983) 80:584-8) and iscurrently used in the treatment of various hyperkinetic disorders. Sideeffects associated with TBZ include sedation, depression, akathisia andparkinsonism. Inhibition of VMAT2 by TBZ results in depletion of brainmonoamines in vivo (see, e.g., Pettibone et al., Eur. J. Pharmacol.(1984) 102:431-6). TBZ also inhibits presynaptic and postsynapticdopamine receptors in rat brain (see, e.g., Login et al., (1982) Ann.Neurology 12:257-62; Reches et al., J. Pharmacol. Exp. Ther. (1983)225:515-521). This off-target activity of TBZ may be responsible forsome of the observed side effects.

TBZ, which contains two chiral centers and is a racemic mix of twostereoisomers, is rapidly and extensively metabolized in vivo to itsreduced form, 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, also known asdihydrotetrabenazine (HTBZ). HTBZ is thought to exist as four individualisomers: namely, (±) alpha-HTBZ and (±) beta-HTBZ. The 2R, 3R,11bR or(+) alpha-HTBZ is believed to be the absolute configuration of theactive metabolite (see, e.g., Kilbourn et al., Chirality (1997),9:59-62). Despite its success in treating hyperkinetic disorders,tetrabenazine has a fairly low and variable bioavailability.Tetrabenazine administration to humans is complicated by extensive firstpass metabolism and little or no tetrabenazine is observed in the urine.

Despite the advances that have been made in this field, a need remainsin the art for improved VMAT2 inhibitors, including compounds,compositions, and methods related thereto. The present disclosurefulfills these and other needs, as evident in reference to the followingdisclosure.

BRIEF SUMMARY

In brief, provided herein is the compound[9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H, 6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol (R¹═H) and relatedanalogs or prodrugs thereof, such compounds having structure (I):

as well as stereoisomers and pharmaceutically acceptable salts orsolvates thereof, wherein R¹ is as defined in more detail below.

In one embodiment, the compound is[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol,or a pharmaceutically acceptable salt or solvate thereof. In a morespecific embodiment, the compound is the hydrochloride salt; namely,[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanolHCl.

In one embodiment, a pharmaceutical composition is provided thatcomprises one or more compounds of structure (I) in combination with apharmaceutically acceptable excipient and/or diluent.

In one embodiment, methods are provided for treating diseases,disorders, or conditions that benefit from inhibiting vesicularmonoamine transporter 2 (VMAT2), including the family of hyperkineticmovement disorders. Accordingly, in one embodiment, methods are providedfor treating a hyperkinetic disorder comprising administering to asubject in need thereof a pharmaceutically effective amount of acompound of structure (I), or a pharmaceutical composition comprisingthe same. In a more specific embodiment, the hyperkinetic disorder isHuntington's disease, tardive dyskinesia, Tourette's syndrome or tics.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To this end, various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds and/or compositions, and are eachhereby incorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the effect of representative compound (Compound 1-1)on dopamine depletion as measured using the locomotor activity (LMA)assay.

FIG. 2 illustrates the effect of a representative compound (Compound1-1) in the conditioned avoidance response (CAR) assay of antipsychoticactivity.

FIG. 3 illustrates the contribution of metabolic pathways to the overallin vitro metabolism of Compound 1-1 and R,R,R-DHTBZ using humanhepatocytes.

DETAILED DESCRIPTION

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the terms have the meaning indicated.

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the presentcompounds may be made and used without these details. In otherinstances, well-known structures have not been shown or described indetail to avoid unnecessarily obscuring descriptions of the embodiments.Unless the context requires otherwise, throughout the specification andclaims which follow, the word “comprise” and variations thereof, suchas, “comprises” and “comprising,” are to be construed in an open,inclusive sense, that is, as “including, but not limited to.” Inaddition, the term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, may “consist of” or “consist essentially of” thedescribed features. Headings provided herein are for convenience onlyand do not interpret the scope or meaning of the claimed embodiments.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment. Thus, the appearances of the phrases “in one embodiment” or“in an embodiment” in various places throughout this specification arenot necessarily all referring to the same embodiment. Furthermore, theparticular features, structures, or characteristics may be combined inany suitable manner in one or more embodiments.

Also, as used in this specification and the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontent clearly dictates otherwise. Thus, for example, reference to “anon-human animal” may refer to one or more non-human animals, or aplurality of such animals, and reference to “a cell” or “the cell”includes reference to one or more cells and equivalents thereof (e.g.,plurality of cells) known to those skilled in the art, and so forth.When steps of a method are described or claimed, and the steps aredescribed as occurring in a particular order, the description of a firststep occurring (or being performed) “prior to” (i.e., before) a secondstep has the same meaning if rewritten to state that the second stepoccurs (or is performed) “subsequent” to the first step. The term“about” when referring to a number or a numerical range means that thenumber or numerical range referred to is an approximation withinexperimental variability (or within statistical experimental error), andthus the number or numerical range may vary between 1% and 15% of thestated number or numerical range. It should also be noted that the term“or” is generally employed in its sense including “and/or” unless thecontent clearly dictates otherwise. The term, “at least one,” forexample, when referring to at least one compound or to at least onecomposition, has the same meaning and understanding as the term, “one ormore.”

In one embodiment, provided herein is[9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H, 6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol (R₁═H), as well asanalogs or prodrugs thereof, such compounds having structure (I):

or a stereoisomer or pharmaceutically acceptable salt or solvatethereof,

wherein:

-   -   R¹ is a) hydrogen;        -   b) —P(═O)(OR³)₂;        -   c) —C(═O)alkyl, wherein alkyl is optionally substituted with            R¹⁰ and/or R²⁰;        -   d) —C(═O)heterocyclyl, wherein heterocyclyl is optionally            substituted with R¹⁰ and/or R²⁰;        -   e) —C(═O)carbocyclyl, wherein carbocyclyl is optionally            substituted with R¹⁰ and/or R²⁰;        -   f) —C(═O)N(R₃)alkyl, wherein alkyl is optionally substituted            with R¹⁰ and/or R²⁰;        -   g) —C(═O)N(R₃)carbocyclyl, wherein carbocyclyl is optionally            substituted with R¹⁰ and/or R²⁰;        -   h) —C(═O)Oalkyl, wherein alkyl is optionally substituted            with R¹⁰ and/or R²⁰; or        -   i) alkyl, wherein alkyl is optionally substituted with R¹⁰            and/or R²⁰;

and wherein,

-   -   each R³ is independently hydrogen or alkyl;    -   each R¹⁰ is independently halo, haloalkyl, cyano, nitro,        trimethylsilanyl, —OR³⁰, —SR³⁰, —OC(O)—R³⁰, —N(R³⁰)₂, —C(O)R³⁰,        —C(O)OR³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)OR³¹, —N(R³⁰)C(O)R³¹,        —N(R³⁰)C(═NR³¹)N(R³²)₂, —N(R³⁰)S(O)_(t)R³¹ (where t is 1 to 2),        —S(O)_(t)OR³⁰ (where t is 1 to 2), —S(O)_(p)R³⁰ (where p is 0        to 2) or —S(O)_(t)N(R³⁰)₂ (where t is 1 to 2), —OP(═O)(OR³⁰)₂,        or when a single atom bears two R¹⁰ groups such two R¹⁰ groups        may be taken together to form oxo;

each R²⁰ is independently alkyl, alkenyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclalkyl, heteroaryl orheteroarylalkyl, or when a single atom bears two R²⁰ groups such two R²⁰groups may be taken together to form cycloalkyl, wherein each of saidalkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclalkyl, heteroaryl and heteroarylalkyl groups isoptionally substituted with R¹⁰ and/or R²²;

each R²² is independently alkyl, alkenyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclalkyl, heteroaryl orheteroarylalkyl, wherein each of said alkyl, alkenyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclalkyl, heteroaryland heteroarylalkyl groups is optionally substituted with R¹⁰; and

each R³⁰, R³¹ and R³² is independently hydrogen or alkyl.

With regard to stereoisomers, the compounds of structure (I) havemultiple chiral (or asymmetric) centers which give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)-. When the compoundsdescribed herein contain olefinic double bonds or other centers ofgeometric asymmetry, and unless specified otherwise, it is intended thatthe compounds include both E and Z geometric isomers (e.g., cis ortrans). Likewise, unless otherwise indicated, all possible isomers, aswell as their racemic and optically pure forms, and all tautomeric formsare also intended to be included. It is therefore contemplated thatvarious stereoisomers and mixtures thereof include “enantiomers,” whichrefers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another. Thus, the compounds may occur in anyisomeric form, including racemates, racemic mixtures, and as individualenantiomers or diastereomers.

Accordingly, and in a more specific embodiment, provided herein is thecompound [(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol(R′═H), as well as analogs or prodrugs thereof, having thestereochemistry noted in structure (II):

or pharmaceutically acceptable salt or solvate thereof, wherein R₁ is asdefined above.

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to twelve carbon atoms, one to eightcarbon atoms, or one to six carbon atoms, or one to four carbon atoms,and which is attached to the rest of the molecule by a single bond,e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl,n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, andthe like.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, having from two to twelve carbon atoms,preferably two to eight carbon atoms and which is attached to the restof the molecule by a single bond, e.g., ethenyl, prop-1-enyl,but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms or from one to four carbon atoms,e.g., methylene, ethylene, propylene, n-butylene, and the like. Thealkylene chain is attached to the rest of the molecule through a singlebond and to the radical group through a single bond. The points ofattachment of the alkylene chain to the rest of the molecule and to theradical group can be through one carbon or any two carbons within thechain.

“Carbocyclyl” refers to a stable 3- to 18-membered aromatic ornon-aromatic ring radical which consists of 3 to 18 carbon atoms. Unlessstated otherwise specifically in the specification, the carbocyclylradical may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem, which may include fused or bridged ring systems, and may bepartially or fully saturated. Non-aromatic carbocyclyl radicals includecycloalkyl, while aromatic carbocyclyl radicals include aryl.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,and which is saturated or unsaturated and attached to the rest of themolecule by a single bond. Monocyclic radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptly, andcyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, 7,7-dimethyl-bicyclo-[2.2.1]heptanyl, and thelike.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. The aryl radicalmay be a monocyclic, bicyclic, tricyclic or tetracyclic ring system,which may include fused or bridged ring systems. Aryl radicals include,but are not limited to, aryl radicals derived from aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. In one embodiment, aryl is phenyl or naphthyl, and inanother embodiment is phenyl.

“Aralkyl” refers to a radical of the formula —R_(b)R_(c) where R_(b) isan alkylene chain as defined herein and R_(c) is one or more arylradicals as defined herein, for example, benzyl, diphenylmethyl and thelike.

“Heterocyclyl” refers to a stable 3- to 18-membered aromatic ornon-aromatic ring radical which consists of two to twelve carbon atomsand from one to six heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur. Unless stated otherwise specifically in thespecification, the heterocyclyl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems; and the nitrogen, carbon or sulfur atoms in theheterocyclyl radical may be optionally oxidized; the nitrogen atom maybe optionally quaternized; and the heterocyclyl radical may be partiallyor fully saturated. Examples or aromatic hetercyclyl radicals are listedbelow in the definition of heteroaryls (i.e., heteroaryl being a subsetof heterocyclyl). Examples of non-aromatic heterocyclyl radicalsinclude, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,pyrazolopyrimidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl,trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl,thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(h) whereR_(b) is an alkylene chain as defined herein and R_(h) is a heterocyclylradical as defined herein, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,benzoxazolinonyl, benzimidazolthionyl, carbazolyl, cinnolinyl,dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl,imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl,isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl,1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl,1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pryrimidinonyl,pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinonyl, quinazolinyl,quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl,thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl,tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl).

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(i) whereR_(b) is an alkylene chain as defined herein and R_(i) is a heteroarylradical as defined herein.

“Cyano” refers to the —CN radical.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined herein, that issubstituted by one or more halo radicals, as defined herein, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Trimethylsilanyl” refers to the —Osi(CH₃)₃ radical.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)Rg whereR_(b) is an alkylene chain as defined herein and R_(g) is a cycloalkylradical as defined herein.

“Fused” refers to any ring system described herein which is fused to anexisting ring structure in the compounds of the invention. When thefused ring system is a heterocyclyl or a heteroaryl, any carbon in theexisting ring structure which becomes part of the fused ring system maybe replaced with a nitrogen.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound, such as compound 1-1 described herein. Thus, the term“prodrug” refers to a metabolic precursor of a compound described hereinthat is pharmaceutically acceptable. A prodrug may be inactive whenadministered to a subject in need thereof, but is converted in vivo toan active compound as described herein. Prodrugs are typically rapidlytransformed in vivo to yield the parent compound described herein, forexample, by hydrolysis in blood. The prodrug compound often offersadvantages of solubility, tissue compatibility or delayed release in amammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985),pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs isprovided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,”A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated in full byreference herein.

In one embodiment, the compounds described herein serve as a prodrug to[9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]-isoquinolin-2-yl]methanol(compound 1-1); that is, the compound may be converted underphysiological conditions to compound 1-1. In another embodiment, thecompounds described herein are themselves VMAT2 inhibitors, and thusactive analogs to compound 1-1.

The compounds described herein may exist in a continuum of solid statesranging from fully amorphous to fully crystalline. Furthermore, some ofthe crystalline forms of the compounds having a structure of formula(I), formula II, and substructures and specific compounds thereof, mayexist as polymorphs. In addition, some of the compounds may also formsolvates with water or other organic solvents. The term solvate is usedherein to describe a molecular complex comprising a compound describedherein and one or more pharmaceutically acceptable solvent molecules.Such solvates are similarly included within the scope of thisdisclosure.

As one of skill in the art would appreciate, any of the compoundsdescribed herein may incorporate radioactive isotopes. Accordingly, alsocontemplated is use of isotopically-labeled compounds identical to thosedescribed herein, wherein one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into these compounds include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but notlimited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and³⁶Cl, respectively. Certain isotopically-labeled compounds, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are also useful in drug or substrate tissue distributionassays. Tritiated hydrogen (³H) and carbon-14 (¹⁴C) isotopes areparticularly preferred for their ease of preparation and detectability.Substitution with heavier isotopes such as deuterium (²H) can providecertain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced doserequirements and, therefore, may be preferred in some circumstances.Isotopically-labeled compounds can generally be prepared by performingprocedures routinely practiced in the art.

In one embodiment, R¹ of structures (I) and (II) is hydrogen, and thecompound has structure (III) or (IV):

In one embodiment, R¹ of structure (I) and (II) is —C(═O)—R², where R²is alkyl, heterocyclyl or carbocyclyl and each of said alkyl,heterocyclyl or carbocyclyl is optionally substituted with R¹⁰ and/orR²⁰ as defined above, and the compound has structure (V) or (VI):

In an embodiment, R₁ of structure (I) and (II) is —C(═O)—O—R₂, where R²is alkyl and said alkyl is optionally substituted with R¹⁰ and/or R²⁰ asdefined above, and the compound has structure (VI) or (VII):

In an embodiment, R₁ of structure (I) and (II) is —C(═O)N(R³)R² where R²is alkyl, heterocyclyl or carbocyclyl and each of said alkyl,heterocyclyl or carbocyclyl is optionally substituted with R¹⁰ and/orR²⁰ as defined above, and the compound has structure (VIII) or (IX):

In an embodiment, R¹ of structure (I) and (II) is alkyl, wherein saidalkyl is optionally substituted with R¹⁰ and/or R²⁰ as defined above,and the compound has structure (X) or (XI):

In an embodiment, R¹ of structure (I) and (II) is —P(═O)(OR³)₂, and thecompound has the structure of formula (XII) or (XIII):

In certain embodiments of compounds having structures (I) through(XIII), wherein the alkyl, heterocyclyl or carbocyclyl of suchstructures is optionally substituted with R¹⁰ and/or R²⁰. Optionalsubstitution in this regard means that the alkyl, heterocyclyl orcarbocyclyl group is either (i) not substituted with R¹⁰ or R²⁰, or (ii)is substituted with one or both of R¹⁰ and R²⁰. When substituted withone or both of R¹⁰ and R²⁰, such substituents may be present singularly(i.e., a single R¹⁰ or R²⁰ substituent), or in multiples (i.e., morethan one R¹⁰ substituent, more than one R²⁰ substituent, or acombination of one or more R¹⁰ substituents, and one or more R²⁰substituents). The total number of R¹⁰ and/or R²⁰ substituents may rangefrom zero (i.e., when the alkyl, heterocyclyl or carbocyclyl isunsubstituted) up to 10 (i.e., when the alkyl, heterocyclyl orcarbocyclyl is substituted). When substituted the total number of R¹⁰and R²⁰ substituents generally range from 1 to 10, or from 1 to 8, orfrom 1 to 6, or from 1 to 4, or from 1 to 2. In those embodiments inwhich the alkyl, heterocyclyl or carbocyclyl is substituted with R²⁰,such R²⁰ substituent may be optionally substituted with R¹⁰ and/or R²²as defined above in the context of R¹⁰ and/or R²⁰. Further, in the caseof R²², such R²² substituent may be optionally substituted with R^(m),again as defined in the context of R¹⁰ above.

In one embodiment, R¹ is —C(═O)alkyl, wherein alkyl is optionallysubstituted with R¹⁰ and/or R²⁰. Representative “OR¹” groups of thisembodiment are labeled “A” in Table 1.

In one embodiment, R¹ is —C(═O)heterocyclyl, wherein heterocyclyl isoptionally substituted with R¹⁰ and/or R²⁰. Representative “OR¹” groupsof this embodiment are labeled “B” in Table 1.

In one embodiment, R¹ is —C(═O)carbocyclyl, wherein carbocyclyl isoptionally substituted with R¹⁰ and/or R²⁰. Representative “OR¹” groupsof this embodiment are labeled “C” in Table 1.

In one embodiment, R¹ is —C(═O)N(R₃)alkyl, wherein alkyl is optionallysubstituted with R¹⁰ and/or R²⁰. Representative “OR¹” groups of thisembodiment are labeled “D” in Table 1.

In one embodiment, R¹ is —C(═O)N(R₃)carbocycle, wherein carbocycle isoptionally substituted with R¹⁰ and/or R²⁰. Representative “OR¹” groupsof this embodiment are labeled “E” in Table 1.

In one embodiment, R¹ is —P(═O)(OR³)₂ and representative “OR¹” groups ofthis embodiment are labeled “F” in Table 1.

In one embodiment, R¹ is —C(═O)Oalkyl, wherein alkyl is optionallysubstituted with R¹⁰ and/or R²⁰. Representative “OR¹” groups of thisembodiment are labeled “G” in Table 1.

In one embodiment, R¹ is alkyl, wherein alkyl is optionally substitutedwith R¹⁰ and/or R²⁰. Representative “OR¹” groups of this embodiment arelabeled “H” in Table 1.

It should be noted that some of the compounds listed in Table 1 may becharacterized by more than one class. For example, compound 5-5 isidentified as a “D” compound, indicating that R¹ is —C(═O)N(R₃)alkyl,wherein alkyl is optionally substituted with R¹⁰ and/or R²⁰ (in thiscase, two R²⁰ groups are taken together to form cyclopropyl). However,compound 5-5 may also be classified as an “E” compound, indicating thatR¹ is —C(═O)N(R₃)carbocycle, wherein carbocycle is optionallysubstituted with R¹⁰ and/or R²⁰. Thus, the classifications below are notmeant to exclude any specific compound from falling within multipleclasses.

Furthermore, in Table 1 (as well as Tables 2-8 below), the monovalentoxygen (“O”) denotes the point of attachment of the “OR₁” substituent tostructure (I), and is not a component of the R¹ group. It should also benoted that, for purpose of abbreviation, some nitrogen atoms aredepicted absent their accompanying hydrogen atoms, such as monovalent“—N” in place of “—NH₂” and divalent “—N—” in place of “—NH—”. Oneskilled in this field will radially recognize and appreciate the meaningof such abbreviated designations.

TABLE 1 Representative R¹ Groups Cpd. O—R¹ 2-1

A 2-2

A 2-3

A 2-4

A 2-5

A 2-6

B 2-7

A 2-8

A 2-9

A 2-10

A 2-11

B 2-12

B 2-13

A 2-14

A 2-15

A 2-16

A 2-17

A 2-18

B 2-19

A 2-20

C 2-21

B 2-22

B 2-23

A 2-24

A 2-25

B 2-26

B 2-27

B 2-28

A 2-29

A 2-30

A 2-31

B 2-32

A 2-33

A 2-34

A 2-35

A 2-36

A 2-37

B 2-38

C 2-39

A 3-1

A 3-2

A 3-3

A 3-4

C 3-5

C 3-6

C 3-7

A 3-8

A 3-9

A 3-10

A 3-11

A 3-12

A 3-13

A 4-1

B 4-2

A 4-3

B 4-4

B 4-5

B 4-6

B 4-7

B 4-8

B 4-9

A 4-10

A 4-11

B 4-12

A 4-13

B 4-14

A 4-15

B 4-16

A 4-17

A 4-18

C 4-19

A 4-20

B 4-21

B 4-22

B 4-23

A 4-24

A 4-25

C 4-26

B 4-27

B 4-28

A 4-29

B 4-30

A 4-31

A 4-32

B 4-33

A 4-34

A 4-35

B 4-36

A 4-37

A 4-38

A 5-1

D 5-2

D 5-3

D 5-4

B 5-5

D 5-6

B 5-7

B 5-8

B 5-9

E 5-10

D 5-11

D 5-12

B 5-13

B 5-14

B 5-15

B 5-16

D 5-17

D 5-18

B 5-19

D 5-20

D 5-21

B 5-22

D 5-23

D 5-24

B 5-25

D 5-26

D 5-27

B 5-28

D 5-29

D 5-30

D 5-31

B 5-32

D 5-33

D 5-34

D 5-35

E 5-36

D 5-37

B 5-38

D 5-39

D 5-40

E 5-41

E 5-42

D 5-43

B 5-44

B 5-45

D 5-46

D 5-47

D 5-48

B 5-49

B 5-50

B 5-51

D 5-52

B 5-53

B 5-54

B 5-55

D 5-56

D 5-57

D 6-1

B 6-2

B 6-3

B 6-4

B 6-5

B 6-6

B 6-7

B 6-8

B 6-9

B 6-10

B 6-11

B 6-12

B 6-13

B 6-14

B 7-1

F 8-1

G 9-1

H 9-2

H 9-3

H 9-4

H 9-5

H 9-6

H 9-7

H 9-8

H 9-9

H 10-1

H 10-2

H 10-3

H 10-4

H 10-5

H 10-6

H 10-7

H

The compounds described herein may be prepared by known organicsynthesis techniques, including the methods described in the Schemeshereafter and in more detail in the Examples.

Alcohol a is condensed with an acid using1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) anddimethylaminopyridine (DMAP) in methylene chloride to give ester c.Alternatively, ester c can be generated by treating alcohol a with anacid chloride.

The chloroformate intermediate b may be generated by treating alcohol awith phosgene or triphosgene. Treatment of b with an alcohol in thepresence of a base such as DMAP generates the carbonate product c.Alternatively, the carbonate c can be generated directly by treating thealcohol a with a pyrocarbonate under DMAP catalysis.

The carbamate c may be generated by treating alcohol a with a carbamoylchloride in methylene chloride in the presence of a base.

Phosphonate c is generated by treating alcohol a with achlorophosphonate and pyridine in methylene chloride. The phosphonicacid c may be generated by removal of the benzyl groups from thephosphonate with palladium on carbon under an atmosphere of hydrogen.Alternatively, the phosphonic acid c can be generated directly withPOCl₃ in water.

Alcohol a is condensed with a BOC protected amino acid using1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) anddimethylaminopyridine (DMAP) in dimethylformamide and methylenechloride, followed by deprotection of the BOC functionality with, forinstance, a 50/50 trifluoroacetic acid/methylene chloride solution togive d. Alternatively, alcohol a may be condensed with a CBZ-protectedamino acid using DCC (1,3-dicyclohexylcarbodiimide) followed bydeprotection of the CBZ functionality by hydrogenation under appropriateconditions.

The compounds described herein may generally be utilized as the freeacid or free base. Alternatively, the compounds may be used in the formof acid or base addition salts. Acid addition salts of the free aminocompounds may be prepared by methods well known in the art, and may beformed from organic and inorganic acids. Suitable organic acids includemaleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic,trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric,gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic,glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acidsinclude hydrochloric, hydrobromic, sulfuric, phosphoric, and nitricacids. Base addition salts included those salts that form with thecarboxylate anion and include salts formed with organic and inorganiccations such as those chosen from the alkali and alkaline earth metals(for example, lithium, sodium, potassium, magnesium, barium andcalcium), as well as the ammonium ion and substituted derivativesthereof (for example, dibenzylammonium, benzylammonium,2-hydroxyethylammonium, and the like). Thus, a “pharmaceuticallyacceptable salt” is intended to encompass any and all acceptable saltforms.

In general, the compounds used in the reactions described herein may bemade according to organic synthesis techniques known to those skilled inthis art, starting from commercially available chemicals and/or fromcompounds described in the chemical literature. “Commercially availablechemicals” may be obtained from standard commercial sources includingAcros Organics (Pittsburgh Pa.), Aldrich Chemical (Milwaukee Wis.,including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton ParkUK), Avocado Research (Lancashire U.K.), BDH Inc. (Toronto, Canada),Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester Pa.), CrescentChemical Co. (Hauppauge N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester N.Y.), Fisher Scientific Co. (Pittsburgh Pa.), FisonsChemicals (Leicestershire UK), Frontier Scientific (Logan Utah), ICNBiomedicals, Inc. (Costa Mesa Calif.), Key Organics (Cornwall U.K.),Lancaster Synthesis (Windham N.H.), Maybridge Chemical Co. Ltd.(Cornwall U.K.), Parish Chemical Co. (Orem Utah), Pfaltz & Bauer, Inc.(Waterbury Conn.), Polyorganix (Houston Tex.), Pierce Chemical Co.(Rockford Ill.), Riedel de Haen AG (Hanover, Germany), Spectrum QualityProduct, Inc. (New Brunswick, N.J.), TCI America (Portland Oreg.), TransWorld Chemicals, Inc. (Rockville Md.), and Wako Chemicals USA, Inc.(Richmond Va.).

Methods known to one of ordinary skill in the art may be identifiedthrough various reference books and databases. Suitable reference booksand treatise that detail the synthesis of reactants useful in thepreparation of compounds of the present disclosure, or providereferences to articles that describe the preparation, include forexample, “Synthetic Organic Chemistry,” John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure,” 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds of the presentdisclosure, or provide references to articles that describe thepreparation, include for example, Fuhrhop, J. and Penzlin G. “OrganicSynthesis: Concepts, Methods, Starting Materials”, Second, Revised andEnlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman,R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford UniversityPress, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations” 2nd Edition(1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced OrganicChemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) JohnWiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern CarbonylChemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's1992 Guide to the Chemistry of Functional Groups” (1992) InterscienceISBN: 0-471-93022-9; Quin, L. D. et al. “A Guide to OrganophosphorusChemistry” (2000) Wiley-Interscience, ISBN: 0-471-31824-8; Solomons, T.W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN:0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2ndEdition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “IndustrialOrganic Chemicals: Starting Materials and Intermediates: An Ullmann'sEncyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73volumes.

Specific and analogous reactants may also be identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the present disclosure is P. H. Stahl & C. G.Wermuth “Handbook of Pharmaceutical Salts,” Verlag Helvetica ChimicaActa, Zurich, 2002.

As mentioned above, the compounds described herein and their salts mayreduce the supply of monoamines in the central nervous system byinhibiting the human monoamine transporter isoform 2 (VMAT2). As such,these compounds and their salts may have utility over a wide range oftherapeutic applications, and may be used to treat a variety ofdisorders which are caused by or linked to inhibition of the humanmonoamine transporter isoform 2. These disorders include hyperkineticdisorders, schizophrenia and bipolar disease.

In an embodiment, conditions which may be treated by compounds describedherein include, but are not limited to, treatment of hyperkineticdisorders such as Huntington's disease, tardive dyskinesia, Tourette'ssyndrome, and tics.

In another embodiment, the compounds described herein and their saltsmay be hydrolyzed in the body of a mammal to compounds that may inhibitthe human monoamine transporter isoform 2. As such, these compounds andtheir salts may have additional utility in altering the in vivoproperties of the metabolite in a mammal such as the maximumconcentration or duration of action.

The compounds described herein, such as[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol(also called Compound 1-1 herein) may be less likely to exhibitpharmacokinetic variability. This reduced variability may be due to areduced interaction with the CYP2D6 related metabolic pathway. Withoutwishing to be bound by theory, such compounds may thus possess lesspotential for drug-drug interaction (DDI) associated with a CYP2D6mechanism.

In another embodiment, pharmaceutical compositions containing one ormore monoamine re-uptake inhibitors (i.e., VMAT2 inhibitors) aredisclosed. For the purposes of administration, the compounds describedherein may be formulated as pharmaceutical compositions. Pharmaceuticalcompositions comprise a monoamine re-uptake inhibitor described hereinand a pharmaceutically acceptable excipient, carrier and/or diluent. TheVMAT2 inhibitor is present in the composition in an amount that iseffective to treat a particular disorder—that is, in an amountsufficient to reduce the supply of monoamines in the central nervoussystem, and preferably with acceptable toxicity to the patient.Appropriate concentrations and dosages can be readily determined by oneskilled in the art.

As understood by a person skilled in the medical art, the terms, “treat”and “treatment,” refer to medical management of a disease, disorder, orcondition of a subject (i.e., patient) (see, e.g., Stedman's MedicalDictionary). The terms “treatment” and “treating” embraces bothpreventative, i.e. prophylactic, or therapeutic, i.e. curative and/orpalliative, treatment. Thus the terms “treatment” and “treating”comprise therapeutic treatment of patients having already developed thecondition, in particular in manifest form. Therapeutic treatment may besymptomatic treatment in order to relieve the symptoms of the specificindication or causal treatment in order to reverse or partially reversethe conditions of the indication or to stop or slow down progression ofthe disease. Thus the compositions and methods described herein may beused, for instance, as therapeutic treatment over a period of time aswell as for chronic therapy. In addition the terms “treatment” and“treating” comprise prophylactic treatment, i.e., a treatment ofpatients at risk to develop a condition mentioned hereinbefore, thusreducing the risk.

The subject in need of the compositions and methods described hereinincludes a subject who has been diagnosed by a person skilled in themedical and psychiatric arts with a hyperkinetic disorder (e.g., tardivedyskinesia). A subject (or patient) to be treated may be a mammal,including a human or non-human primate. The mammal may be a domesticatedanimal such as a cat or a dog.

Therapeutic and/or prophylactic benefit includes, for example, animproved clinical outcome, both therapeutic treatment and prophylacticor preventative measures, wherein the object is to prevent or slow orretard (lessen) an undesired physiological change or disorder, or toprevent or slow or retard (lessen) the expansion or severity of suchdisorder. Prophylactic administration of a composition herein maycommence upon first treatment with dopamine receptor blocking drugs suchas neuroleptics. As discussed herein, beneficial or desired clinicalresults from treating a subject include, but are not limited to,abatement, lessening, or alleviation of symptoms that result from or areassociated the disease, condition, or disorder to be treated; decreasedoccurrence of symptoms; improved quality of life; longer disease-freestatus (i.e., decreasing the likelihood or the propensity that a subjectwill present symptoms on the basis of which a diagnosis of a disease ismade); diminishment of extent of disease; stabilized (i.e., notworsening) state of disease; delay or slowing of disease progression;amelioration or palliation of the disease state; and remission (whetherpartial or total), whether detectable or undetectable; and/or overallsurvival. “Treatment” can also mean prolonging survival when compared toexpected survival if a subject were not receiving treatment. Subjects inneed of treatment include those who already have the condition ordisorder as well as subjects prone to have or at risk of developing thedisease, condition, or disorder (e.g., TD or other conditions ordisorders described herein), and those in which the disease, condition,or disorder is to be prevented (i.e., decreasing the likelihood ofoccurrence of the disease, disorder, or condition). A therapeuticallyeffective amount of any one of the compounds described herein in theamount of the compound that provides a statistically or clinicallysignificant therapeutic and/or prophylactic benefit to the treatedsubject.

Methods for determining the effectiveness of a therapeutic for treatinga hyperkinetic disorder are routinely practiced in the art by a personskilled in the medical and clinical arts. By way of example, a subjectwith a hyperkinetic disorder may be diagnosed, monitored, and evaluatedby the Abnormal Involuntary Movement Scale (AIMS). The AIMS is astructured neurological examination that was developed in 1976 and hasbeen used extensively in movement disorder assessments. It consists ofseven distinct ratings of regional involuntary body movements that arescored on a zero to four scale with zero being rated as none and fourbeing rated as severe.

Characterizing any of the compounds having a structure of formula (I),(II), including any substructures and specific compounds thereof, may bedetermined using methods described herein and in the art. For example,dopamine depletion may be determined using the locomotor activity (LMA)assay. Another in vivo animal model includes the conditioned avoidanceresponse (CAR) test, which has been shown to be an effective andreliable preclinical model for assessing the antipsychotic activity ofcompounds.

The present disclosure further provides for pharmaceutical compositionscomprising any one of the compounds described herein (a compound ofFormula I, Formula II, and including all substructures and specificcompounds described herein) and a pharmaceutically acceptable excipientfor use in the methods for treating neurological disorders and diseases,such as hyperkinetic disorders.

Pharmaceutically acceptable carriers and/or diluents are familiar tothose skilled in the art. For compositions formulated as liquidsolutions, acceptable carriers and/or diluents include saline andsterile water, and may optionally include antioxidants, buffers,bacteriostats and other common additives. The compositions can also beformulated as pills, capsules, granules, or tablets which contain, inaddition to a VMAT2 inhibitor, diluents, dispersing and surface activeagents, binders, and lubricants. One skilled in this art may furtherformulate the VMAT2 inhibitor in an appropriate manner, and inaccordance with accepted practices, such as those disclosed inRemington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co.,Easton, Pa. 1990.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.The pharmaceutical compositions may also be formulated as a suspension,solid, semi-solid, or thixotropic liquid, for administration as animplanted depot.

In another embodiment, a method is provided herein for treatingdisorders of the central or peripheral nervous system. Such methodsinclude administering a compound described herein to a warm-bloodedanimal (e.g., a human) in an amount sufficient to treat the condition.In this context, “treat” includes prophylactic administration. Suchmethods include systemic administration of a VMAT2 inhibitor describedherein, preferably in the form of a pharmaceutical composition asdiscussed above. As used herein, systemic administration includes oraland parenteral methods of administration. For oral administration,suitable pharmaceutical compositions include powders, granules, pills,tablets, and capsules as well as liquids, syrups, suspensions, andemulsions. These compositions may also include flavorants,preservatives, suspending, thickening and emulsifying agents, and otherpharmaceutically acceptable additives. For parental administration, thecompounds described herein can be prepared in aqueous injectionsolutions which may contain, in addition to the VMAT2 inhibitor,buffers, antioxidants, bacteriostats, and other additives commonlyemployed in such solutions.

EXAMPLES Analytical Method—Ultra-High Performance Liquid Chromatography(UPLC-MS)

Platform: Agilent 1260 series UPLC: equipped with an auto-sampler, an UVdetector (220 nM and 254 nM), column thermostat, a MS detector(electrospray);

Column: Waters)(Bridge BEH C18 XP, 2.5 micron, 3×50 mm;

Mobile phase: A=water, 0.025% TFA; B=acetonitrile, 0.025% TFA;

Flow rate: 1.5 mL/min;

Gradient: 10% B/90% A to 90% B/10% A over 1.5 min, then hold 0.3 min,return to initial conditions for 0.5 min; total run time 2.5 min;

For purpose of abbreviation, some nitrogen atoms and/or oxygen atoms aredepicted in the following Examples absent their accompanying hydrogenatoms, such as monovalent “—N” in place of “—NH₂” and “—O” in place of“—OH”, and divalent “—N—” in place of “—NH—”. One skilled in this fieldwill radially recognize and appreciate the meaning of such abbreviateddesignations.

Example 1 Synthesis of[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanolHCl Salt

Step 1A:(3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-carbonitrile(1a)

To a 3 L 3 neck round bottomed flask DMSO (1.1 L) and TOSMIC (104 g,532.5 mmol, 1.3 eq) were charged. To this mixture KO-t-Bu (119.5 g,1.065 mol) was charged at once at ambient temp (22° C.). An exotherm wasobserved and the temperature of the mixture increased to 39° C. Then asuspension of tetrabenazine (130 g, 410 mmol) in DMSO (500 mL) was addedto the reaction mixture slowly over 25 min (a slight exotherm observed).EtOH (10.5 mL) was added to this mixture and the mixture was stirred atambient temp for 3 h. LC-MS analysis of the mixture revealed presence of˜4:1 ratio of 1a and starting material. The mixture was poured into coldwater (9 L). The mixture was then extracted with EtAOc (4 L). Theaqueous layer was extracted with EtOAc (2 L). The combined organics werewashed with brine (2 L), dried over Na₂SO₄ and concentrated. The residuewas dissolved in ace tone (200 ml) and loaded onto a silica column (2 Kgsilica gel, packed with hexanes). The column was eluted first withhexanes (2.5 L), followed by 5-20% of acetone in hexanes. The fractionscontaining 1a and other impurities were combined and concentrated togive an orange oil (72 g) which was dissolved in acetone (100 ml) andloaded onto a silica column (1 Kg silica gel, packed with hexanes). Thecolumn was eluted first with hexanes (1 L), followed by 5% of acetone inhexanes (2 L), 10% of acetone in hexanes (2 L), 15% of acetone inhexanes (2 L), and 20% of acetone in hexanes (2 L). The fractionscontaining >90% purity were combined and concentrated to give(3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-carbonitrile1a as an orange solid (61 g, m/z 329.2 [MH⁺]). The fractions containinga mixture of 1a and starting material were collected and concentrated togive 48 g of material which was dissolved in DMSO (50 ml) and was addedto a mixture of TOSMIC (25 g) and KO-t-Bu (28.7 g) in DMSO (250 ml) asshown above. The residue was dissolved in acetone (10 ml) and loadedonto a silica column (600 g silica gel, packed with hexanes). The columnwas eluted first with hexanes (800 ml), followed by 5-20% of acetone inhexanes. The fractions containing product were combined and concentratedto give orange solid 1a (33 g).

Step 1B:(3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-carboxylicacid (1b)

A 1 gallon pressure reactor was charged with a suspension of 1a (94 g,286 mmol) in methanol (940 ml) and NaOH (343 g, 8.6 mol) in water (940ml). This mixture was stirred at 120° C. (internal temp) for 67 h. Themixture was cooled to room temp and transferred to a round bottom flask.The mixture was concentrated in a rotavap to ˜1 L. The mixture was thenadjusted pH to 7 using aqueous 6N HCl under cooling. The mixture wasextracted with DCM (2×3 L and 1×2 L). The combined organics were driedover Na₂SO₄ and concentrated to give a dark residue (88 g). The darkresidue was taken in acetonitrile (500 ml) and stirred for 30 min. Themixture was filtered and the solid was washed with acetonitrile (50 ml).The solid was dried under vacuum for 2 h to afford light brown solid (42g, 49%). This solid was combined with the filtrate and concentrated to aresidue. The residue was dissolved in DCM (150 ml) and loaded onto asilica column packed with DCM. The column was eluted with 0-25% ofmethanol in DCM. The fractions containing product were combined andconcentrated to give(3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-carboxylicacid 1b as a give pale brown solid (71 g, 71% yield, 92% purity, m/z348.2 [MH⁺]).

Step 1C:(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol(1-1)

A 3 L round bottom flask was charged with 1b (73.5 g, 211.5 mmol) andTHF (1.48 L). This mixture was stirred and cooled to 10° C. (internaltemp). To this mixture was added 1 M LAH in THF (423 ml, 423 mmol)slowly over 20 min keeping the temp below 20° C. The cooling bath wasremoved and the mixture was warmed up to room temp. The mixture washeated to 55° C. and stirred for 30 min. The mixture was cooled to roomtemp and then to 10° C. EtOAc (30 ml) was added slowly to quenchun-reacted LAH followed by ethanol (30 ml). Then water (150 ml) wasadded to this mixture. The mixture was then concentrated to remove mostof organic solvents. Then the mixture was diluted with water (700 ml)and DCM (1 L). The suspension was filtered through a pad of celite. Thefiltered cake was washed with DCM (2×500 ml). The combined filtrateswere taken in separatory funnel and the layers separated. The aqueouslayer was extracted with DCM (1 L). The combined organics were driedover Na₂SO₄ and concentrated to give a dark residue. The residue waschromatographed on silica column using 0-10% of methanol in DCM aseluent. The fractions containing product were combined and concentratedto afford foamy orange residue. To this residue hexanes (100 ml) wasadded and concentrated under reduced pressure at 45° C. for 2 h toafford[(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol1-1 as a pale brown solid (51 g, 72%, 95% HPLC purity by 220 nm, m/z334.2 [MH⁺]). This material may be further purified by silica gelchromatography using 0-10% of methanol in DCM or ethyl acetate aseluent.

Step 1D: [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanolHCl salt (1-1 HCl)

A 2 L round bottom flask was charged with 1-1 (43 g, 129 mmol) anddiethyl ether (860 mL). This mixture was stirred and cooled to 15° C.(internal temp). To this mixture was added 2 M HCl in diethyl ether (97ml, 193 mmol) slowly over 15 min. A white precipitate formed. Thecooling bath was removed and the mixture was warmed to room temp. Themixture was then stirred for 45 min. The mixture was filtered and thefiltered solid was washed with diethyl ether (100 ml), with MTBE (100ml) and then with hexanes (100 ml). The solid was then dried in vacuumoven at 40° C. for 18 h. [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanolHCl salt 1-1 HCl was isolated as an off-white solid (44.7 g, 94% yield,m/z 334.2 [MH⁺]).

Example 2[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methyl3-carbamoylpropanoate

Step 2A

[(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanolHCl salt (20.0 mg, 0.054 mmol) and 3-carbamoylpropanoic acid (7.6 g,0.065 mmol) was dissolved in DCM (0.7 mL) followed byN,N-dimethylpyridin-4-amine (7.9 mg, 0.065 mmol),N,N′-dicyclo-hexylmethanediimine (13.0 mg, 0.065 mmol), andtrimethylamine (0.037 mL, 0.27 mmol) and the reaction was stirredovernight. The crude reaction mixture was diluted with 0.3 mL MeOH andpurified via HPLC yielding[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methyl3-carbamoylpropanoate 2-1 (m/z 433.1 [MH⁺]).

Table 2 below provides the observed (Obs) ion m/z ratio of the othercompounds that were made according to the procedure as described in thisexample.

TABLE 2

Calc Obs Cpd. —O—R¹ Name mass mass 2-1

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3-carbamoylpropanoate 432.26 433.1 2-2

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl3-(morpholin- 4-yl)propanoate 474.31 475.2 2-3

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl3-(2,4-dioxo- 1,2,3,4-tetrahydroquinazolin-3- yl)propanoate 549.28 550.22-4

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3-(dimethylcarbamoyl)propanoate 460.29 461.1 2-5

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3-ethanesulfonamidopropanoate 496.26 497.2 2-6

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (3R)-1-benzylpyrrolidine-3-carboxylate 520.33 521.2 2-7

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3-(dimethylamino)propanoate 432.3 433.2 2-8

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]acetate 488.33 489.3 2-9

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2-carbamoylacetate 418.25 419.1 2-10

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2-[1-methylpyrrolidin-3-yl)acetate 458.31 459.3 2-11

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (3R)-1-benzylpiperidine-3-carboxylate 534.35 535.3 2-12

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 1-methylpiperidine-3-carboxylate 458.31 4459.3 2-13

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl3-(1H-1,2,3,4- tetrazol-1-yl)propanoate 457.27 458.1 2-14

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3-nitropropanoate 434.24 435.1 2-15

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3-(4-methylpiperazin-1-yl)propanoate 487.34 488.3 2-16

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl3-(propane-2- sulfonamido)propanoate 510.28 511.2 2-17

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2,2-dimethylpropanoate 417.29 418.31 2-18

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3-methyloxetane-3-carboxylate 431.27 432.32 2-19

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl3-(piperidin-1- yl)propanoate 472.33 473.2 2-20

[(3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl benzoate437.26 438.28 2-21

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 1-benzylazetidine-3-carboxylate 506.31 507.2 2-22

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl oxane-4-carboxylate 445.28 446.33 2-23

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl3-(3-methyl- 1H-pyrazol-1-yl)propanoate 469.29 470.2 2-24

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl2-hydroxy-2- methylpropanoate 419.27 420.24 2-25

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 1-methylpiperidine-4-carboxylate 458.31 459.2 2-26

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (3S)-1-benzylpyrrolidine-3-carboxylate 520.33 521.2 2-27

[3-({[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)- 2,2,5,5-tetramethylpyrrolidin-1-yl]oxidanyl 501.33 502.2 2-28

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3-methyl-3-(1H-pyrrol-1-yl)butanoate 482.31 483.2 2-29

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl3-(5-methyl- 1H-pyrazol-1-yl)propanoate 469.29 470.2 2-30

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2-(2,5-dioxoimidazolidin-4-yl)acetate 473.25 474.1 2-31

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (4S)-2,6-dioxo-1,3-diazinane-4-carboxylate 473.25 474.3 2-32

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3-(diethylamino)propanoate 460.33 461.1 2-33

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl2-[(4S)-2,5- dioxoimidazolidin-4-yl]acetate 473.25 474.1 2-34

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl hexanoate431.3 432.35 2-35

2- {[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a[isoquinolin-2-yl]methoxy}-2-oxoethane-1-sulfonic acid 455.2 456.16 2-36

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 4-(dimethylamino)butanoate 446.31 447.1 2-37

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 1-methanesulfonylpiperidine-3-carboxylate 522.28 523.2 2-38

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2,2,3,3-tetramethylcyclopropane-1-carboxylate 457.32 458.38 2-39

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl3-(2-oxo-2,3- dihydro-1,3-benzoxazol-3-yl)propanoate 522.27 523.2

Example 35-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methoxy}-3,3-dimethyl-5-oxopentanoicacid

Step 3A

[(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanolHCl salt (9.2 mg, 0.025 mmol), 4,4-dimethyloxane-2,6-dione (3.6 mg,0.025 mmol), N,N-dimethylpyridin-4-amine (1.0 mg, 0.008 mmol), andethylbis(propan-2-yl)amine (0.018 mL, 0.10 mmol) were combined in 0.7 mLof DCM and heated to 50° C. overnight. The reaction mixture was dilutedwith 0.4 mL acetonitrile and purified by HPLC yielding5-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methoxy}-3,3-dimethyl-5-oxopentanoicacid 3-1 (m/z 476.1 [MH⁺]).

Table 3 below provides the observed (Obs) ion m/z ratio of the othercompounds that were made according to the procedure as described in thisexample.

TABLE 3

Calc Obs Cpd. —O—R¹ Name mass mass 3-1

5-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}-3,3-dimethyl-5-oxopentanoic acid 475.29 476.1 3-2

3-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}-3-oxopropanoic acid 419.23 420.1 3-3

5-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methoxy}-3-methyl-5- oxopentanoic acid 461.28 462.23-4

2-({[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)cyclopropane-1- carboxylic acid 445.25 446.1 3-5

2-({[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)cyclohexane-1- carboxylic acid 487.29 488.2 3-6

2-({[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)cyclohexane-1- carboxylic acid 487.29 488.2 3-7

4-{[(3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}-2,2-dimethyl-4-oxobutanoic acid 461.28 462.13 3-8

5-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}-5-oxopentanoic acid 447.26 448.2 3-9

2-[1-(2-{[(2R,3S,11bR)-9,10-dimethoxy- 3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}-2-oxoethyl)cyclopentyl]acetic acid 501.31 502.2 3-10

6-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}-6-oxohexanoic acid 461.28 462.2 3-11

4-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}-3,3-dimethyl-4-oxobutanoic acid 461.28 462.22 3-12

5-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}-2,2-dimethyl-5-oxopentanoic acid 475.29 476.15 3-13

4-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}-4-oxobutanoic acid 433.25 434.18

Example 4 Synthesis of[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methylpiperidine-4-carboxylate

Step 4A

[(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanolHCl salt (9.2 mg, 0.025 mmol),1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid (7.8 mg, 0.034mmol), N,N′-dicyclo-hexylmethanediimine (6.2 mg, 0.03 mmol),N,N-dimethylpyridin-4-amine (3.0 mg, 0.025 mmol), andethylbis(propan-2-yl)amine (0.02 mL, 0.1 mmol) were combined in DCM (1mL) and the reaction was stirred overnight. The reaction was filtered,concentrated, and redissolved in DCM (1 mL). Next, TFA (0.050 mL) wasadded and the reaction stirred for one hour. The reaction wasconcentrated and redissolved in MeOH (1 mL) and purified by HPLC to give[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methylpiperidine-4-carboxylate 4-1 (m/z 445.2 [MH⁺]).

Table 4 below provides the observed (Obs) ion m/z ratio of the othercompounds that were made according to the procedure as described in thisexample.

TABLE 4

Calc Obs Cpd. —O—R¹ Name mass mass 4-1

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methylpiperidine-4- carboxylate 444.3 445.2 4-2

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl(2S)-2-amino- 3-phenylpropanoate 480.3 481.3 4-3

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (3S)-morpholine-3-carboxylate 446.28 447.2 4-4

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (1R,2R)-2-aminocyclohexane-1-carboxylate 458.31 459.2 4-5

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (3R)-morpholine-3-carboxylate 446.28 447.1 4-6

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl2,3-dihydro- 1H-isoindole-1-carboxylate 478.28 479.3 4-7

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (3S)-pyrrolidine-3-carboxylate 430.28 431.2 4-8

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methylpyrrolidine-3- carboxylate 430.28 431.2 4-9

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2-[1-(aminomethyl)cyclohexyl]acetate 486.35 487.2 4-10

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl2-(piperidin-3- yl)acetate 458.31 459.2 4-11

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2-aminocyclopentane-1-carboxylate 444.3 445.1 4-12

[(3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl(2S)-2-amino- 3-methylbutanoate 432.3 433.3 4-13

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (3S)-piperidine-3-carboxylate 444.3 445.1 4-14

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2-(1-aminocyclohexyl)acetate 472.33 473.3 4-15

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3-methylpiperidine-4-carboxylate 458.31 459.3 4-16

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl2-(pyrrolidin- 3-yl)acetate 444.3 445.3 4-17

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3-amino-4-methylpentanoate 446.31 447.3 4-18

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 4-(aminomethyl)benzoate 466.28 467.3 4-19

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl2-amino-2-(2- methoxyphenyl)acetate 496.29 497.3 4-20

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methylpiperidine-3- carboxylate 444.3 445.1 4-21

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 1,2,3,4-tetrahydroisoquinoline-1-carboxylate 492.3 493.3 4-22

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 4-methoxypiperidine-4-carboxylate 474.31 475.2 4-23

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2-[(2R)-pyrrolidin-2-yl]acetate 444.3 445.1 4-24

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3-aminopropanoate 404.27 405.2 4-25

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (1S,2S)-2-aminocyclohexane-1-carboxylate 458.31 459.2 4-26

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (3R)-pyrrolidine-3-carboxylate 430.28 431.2 4-27

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methylmorpholine-2- carboxylate 446.28 447.1 4-28

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl2-(pyrrolidin- 2-yl)acetate 444.3 445.1 4-29

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (3R)-piperidine-3-carboxylate 444.3 445.1 4-30

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl(2R)-2-amino- 2-[4-(trifluoromethyl)phenyl]acetate 534.27 535.3 4-31

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 4-aminobutanoate 418.28 419.2 4-32

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methylmorpholine-3- carboxylate 446.28 447.2 4-33

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl(2S)-2-amino- 2-phenylacetate 466.28 467.3 4-34

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl2-(piperidin-2- yl)acetate 458.31 459.2 4-35

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 4-methylpiperidine-4-carboxylate 458.31 459.2 4-36

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2-[(2S)-pyrrolidin-2-yl]acetate 444.3 445.1 4-37

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl3-(piperazin-1- yl)propanoate 473.33 474.3 4-38

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2-[(3R)-pyrrolidin-3-yl]acetate 444.3 445.3

Example 53-[({[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methoxy}carbonyl)amino]propanoicacid

Step 5A

[(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanolHCl salt (300 mg, 0.81 mmol) and 4-nitrophenyl chloroformate (246 mg,1.22 mmol) were dissolved in DCM and cooled to 0° C.Ethylbis(propan-2-yl)amine (0.54 mL, 3.25 mmol) was then added, warmedto room temperature, and stirred overnight. The crude reaction mixturewas then concentrated and purified by column chromatography (0% to 100%EtOAc in hexanes) to afford[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methyl4-nitrophenyl carbonate 5a (360 mg, 0.722 mmol) as a pale yellow foam in89% yield (m/z 499.2 [MH⁺]).

Step 5B

[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methyl4-nitrophenyl carbonate (12 mg, 0.025 mmol), 3-aminopropanoic acid (3.0mg, 0.030 mmol) and ethylbis(propan-2-yl)amine (0.017 mL, 0.10 mmol)were dissolved in DMF (0.5 mL) and heated to 50° C. overnight. The crudereaction was then diluted with MeOH (0.5 mL) and purified by HPLCyielding3-[({[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methoxy}carbonyl)amino]propanoicacid 5-1 (m/z 449.1 [MH⁺]).

Table 5 below provides the observed (Obs) ion m/z ratio of the othercompounds that were made according to the procedure as described in thisexample.

TABLE 5

Calc Obs Cpd. —O—R¹ Name mass mass 5-1

3-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amin]propanoic acid 448.26 449.1 5-2

(3S)-3-{[({[(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]methyl}-5- methylhexanoic acid 518.34 519.25-3

4-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]butanoic acid 462.27 463.1 5-4

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2-[(dimethylamino)methyl]morpholine-4- carboxylate 503.34 504.2 5-5

1-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]cyclopropane- 1-carboxylic acid 460.26 461 5-6

2-[4-({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)morpholin-2- yl]acetic acid 504.28 505.2 5-7

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 4-methylpiperazine-1-carboxylate 459.31 460.13 5-8

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3-oxopiperazine-1-carboxylate 459.27 459.3 5-9

(1R,2S,3R,4S)-3-[({[(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]bicyclo[2.2. 1]hept-5-ene-2-carboxylic acid512.29 513.2 5-10

4-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]-3- hydroxybutanoic acid 478.27 479.1 5-11

3-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-(1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]-2- hydroxypropanoic acid 464.25 465.1 5-12

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2,2,4-trimethylpiperazine-1-carboxylate 487.34 5-13

1-({[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)azetidine-2- carboxylic acid 460.26 461.1 5-14

1-({[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)piperidine-3- carboxylic acid 488.29 489.1 5-15

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 4-methanesulfonylpiperazine-1-carboxylate 523.27 524.15 5-16

2-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)(methyl)amino]-2- methylpropanoic acid 476.29 5-17

(2R)-2-[({[(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy{carbonyl)(methyl)amino] propanoic acid 462.27 463.1 5-18

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 4-cyclohexylpiperazine-1-carboxylate 527.37 528.25 5-19

(3R)-3-{[({[(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]methyl}-5- methylhexanoic acid 518.34 519.255-20

(2S)-2-[({[(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]-4- methylpentanoic acid 490.3 491.2 5-21

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2-methyl-3oxopiperazine-1-carboxylate 473.29 474.2 5-22

3-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]-3- methylbutanoic acid 476.29 477.1 5-23

1-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]cyclohexane- 1-carboxylic acid 502.3 503.25-24

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl(1S,4S)-2-oxa- 5-azabicyclo[2.2.1]heptane-5-carboxylate 458.28 459.25-25

4-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)(methyl)amino] butanoic acid 476.29 477.1 5-26

3-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]butanoic acid 462.27 463.15 5-27

1-({[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)azetidine-3- carboxylic acid 460.26 461.0 5-28

2-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)(methyl)amino] propanoic acid 462.27 463.2 5-29

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl N,N-dimethylcarbamate 404.27 405.32 5-30

2-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]acetic acid 434.24 435.1 5-31

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl4-(propan-2- yl)piperazine-1-carboxylate 487.34 488.2 5-32

2-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)(methyl)amino]-3- methylbutanoic acid 490.3 491.25-33

(2S)-2-[({[(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)(methyl)amino] propanoic acid 462.27 463.1 5-34

2-(1-{[({[(2R,3S,11bR)-9,10-dimethoxy- 3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]methyl} cyclohexyl)acetic acid 530.34 531.25-35

(1R,2R)-2-[({[(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]cyclohexane- 1-carboxylic acid 502.3 503.25-36

4-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]-3,3- dimethylbutanoic acid 490.3 491.2 5-37

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (2R)-2-methylmorpholine-4-carboxylate 460.29 461.1 5-38

3-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]-2,2- dimethylpropanoic acid 476.29 477.1 5-39

1-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]cyclopentane- 1-carboxylic acid 488.29 489.35-40

3-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]bicyclo[2.2. 1]heptane-2-carboxylic acid 514.3515.2 5-41

2-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]cyclohexane- 1-carboxylic acid 502.3 503.25-42

2-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)(methyl)amino] acetic acid 448.26 449.1 5-43

1-({[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methoxy}carbonyl)-4-(dimethylamino)piperidine-4-carboxylic acid 531.33 532.3 5-44

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (2S)-2-methylmorpholine-4-carboxylate 460.29 461.1 5-45

(2R)-2-[({[(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]propanoic acid 448.26 449.1 5-46

2-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)(methyl)amino]-4- methylpentanoic acid 504.32 505.25-47

(2S)-2-[({[(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]propanoic acid 448.26 449.1 5-48

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyldecahydropiperazino[1,2-a]azepine-2- carboxylate 513.36 514.2 5-49

1-({[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)pyrrolidine-3- carboxylic acid 474.27 475.2 5-50

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (2R)-2,4-dimethylpiperazine-1-carboxylate 473.33 474.2 5-51

2-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]-2- methylpropanoic acid 462.27 463.2 5-52

1-({[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)piperidine-4- carboxylic acid 488.29 489.2 5-53

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl(2R,6S)-2,6- dimethylmorpholine-4-carboxylate 474.31 475.2 5-54

(3R)-1-({[(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)piperidine-3- carboxylic acid 488.29 489.2 5-55

3-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)(methyl)amino] propanoic acid 462.27 463.2 5-56

(2S)-4-[({[(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]-2- hydroxybutanoic acid 478.27 479.1 5-57

3-[({[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)amino]-2- methylpropanoic acid 462.27 463.2

Example 6[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methylpiperazine-1-carboxylate

Step 6A

[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methyl4-nitrophenyl carbonate 5a (12 mg, 0.025 mmol), tert-butylpiperazine-1-carboxylate (6.0 mg, 0.030 mmol) andethylbis(propan-2-yl)amine (0.017 mL, 0.10 mmol) were dissolved in DCM(0.5 mL) and allowed to stir overnight. Next, TFA (0.050 mL) was addedand stirred for 4 hours. The crude reactions were then diluted with MeOH(0.5 mL) and purified by HPLC yielding[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methylpiperazine-1-carboxylate 6-1 (m/z 446.2 [MH⁺]).

Table 6 below provides the observed (Obs) ion m/z ratio of the othercompounds that were made according to the procedure as described in thisexample.

TABLE 6

Calc Obs Cpd. —O—R¹ Name mass mass 6-1

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methylpiperazine-l- carboxylate 445.29 446.2 6-2

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl(2R,5S)-2,5- dimethylpiperazine-l-carboxylate 473.33 474.2 6-3

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (2R)-2-methylpiperazine-1-carboxylate 459.31 460.2 6-4

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate 471.31 472.2 6-5

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (2S)-2-methylpiperazine-1-carboxylate 459.31 460.2 6-6

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl(3R,5S)-3,5- dimethylpiperazine-1-carboxylate 473.33 474.3 6-7

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (2R)-2-(hydroxymethyl)piperazine-1- carboxylate 475.3 476.1 6-8

(2R)-4-({[(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}carbonyl)piperazine-2- carboxylic acid 489.28 490.2 6-9

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (3S)-3-cyanopiperazine-1-carboxylate 470.29 471.2 6-10

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl(1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate 457.29 458.2 6-11

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 3,5-dimethylpiperazine-1-carboxylate 473.33 474.2 6-12

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl(2R,6S)-2,6- dimethylpiperazine-1-carboxylate 473.33 6-13

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl (3R)-3-methylpiperazine-1-carboxylate 459.31 460.1 6-14

[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methyl 2,5-dimethylpiperazine-1-carboxylate 473.33 474.2

Example 7[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methyldiethyl phosphate

Step 7A

[(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanolHCl salt (100 mg, 0.27 mmol) and diethyl chlorophosphonate (140 mg, 0.81mmol) were dissolved in DCM (2 mL) then ethylbis(propan-2-yl)amine (0.18mL, 1.1 mmol) was added and the reaction mixture stirred overnight. Thecrude reaction mixture was diluted with DCM (10 mL), washed with sat.NH₄Cl (5 mL) then sat. NaHCO₃ (5 mL), dried over MgSO₄, filtered andconcentrated. The crude mixture was purified by column chromatography(0% to 5% MeOH in DCM) to afford[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methyldiethyl phosphate 7-1 (69.0 mg, 0.15 mmol) in a 56% yield. Next the HCLsalt was made using 1N HCl in ether (0.16 mL, 0.16 mmol) (m/z 470.8[MH⁺]).

Example 8[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methylpropan-2-yl carbonate

Step 8A

[(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanolHCl salt (150 mg, 0.41 mmol) was dissolved in pyridine (12 mL) andcooled to −50° C. Next, propan-2-yl chloroformate (1M) (8.1 mL, 8.1mmol) was added dropwise. The reaction was stirred at 0° C. for threehours. The crude reaction mixture was diluted with EtOAc (50 mL), washedwith sat. NH₄Cl (20 mL), dried with MgSO₄, filtered and concentrated.The crude reaction mixture was purified by column chromatography (0% to5% MeOH in DCM) to afford[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methylpropan-2-yl carbonate (100 mg, 0.24 mmol) in a 59% yield (m/z 420.3[MH⁺]).

Example 9(2R,3S,11bR)-9,10-Dimethoxy-2-(methoxymethyl)-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline

Step 9A

[(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanolHCl salt (15 mg, 0.041 mmol) was dissolved in anhydrous DMF (0.5 mL) andNaH (32 mg, 0.82 mmol) was added and heated to 80° C. The mixture wascooled to 0° C. and MeI (0.003 mL, 0.041 mmol) was added and stirred for1 hour. The reaction was quenched with sat. NH₄Cl (0.5 mL) and extractedwith EtOAc (10 mL), the crude reaction mixture was concentrated,redissolved in MeOH (1 mL) and purified by HPLC (m/z 348.1 [MH⁺])yielding(2R,3S,11bR)-9,10-dimethoxy-2-(methoxymethyl)-3-(2-methylpropyl)-1H,2H,3H,4H,6H, 7H,11bH-pyrido[2,1-a]isoquinoline 9-1.

Table 7 below provides the observed (Obs) ion m/z ratio of the othercompounds that were made according to the procedure as described in thisexample.

TABLE 7

Calc Obs Cpd. —O—R¹ Name mass mass 9-1

(2R,3S,11bR)-9,10-dimethoxy-2- (methoxymethyl)-3-(2-methylpropyl)-347.25 348.1 1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinoline 9-2

(2R,3S,11bR)-2-[(2- fluoroethoxy)methyl]-9,10-dimethoxy-3- 379.25 380.2(2-methylpropyl)- 1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinoline 9-3

2-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}-1-(4-fluorophenyl)ethan-1-one 469.26 470.15 9-4

(2R,3S,11bR)-9,10-dimethoxy-2- [(²H₃)methoxymethyl]-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- 350.26 351.3 a]isoquinoline 9-5

(2R,3S,11bR)-9,10-dimethoxy-2- [(methoxymethoxy)methyl]-3-(2- 377.26378.3 methylpropyl)- 1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinoline9-6

(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-2-[(2,2,2-trifluoroethoxy)methyl]- 1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline 415.23 416.2 9-7

(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-2-[(3,3,3-trifluoropropoxy)methyl]- 1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline 429.25 430.4 9-8

(2R,3S,11bR)-2-(ethoxymethyl)-9,10- dimethoxy-3-(2-methylpropyl)- 361.26362.1 1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinoline 9-9

(2R,3S,11bR)-9,10-dimethoxy-2-[(2- methylpropoxy)methyl]-3-(2-methylpropyl)- 389.29 390.2 1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline

Example 10 Benzyl4-(2-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methoxy}-2-oxoethyl)piperidine-1-carboxylate

Step 10A

[(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanolHCl salt (250 mg, 0.68 mmol) was dissolved in DCM (5 mL) and2-{1-[(benzyloxy)carbonyl]piperidin-4-yl}acetic acid (244 mg, 0.88mmol), DCC (181 mg, 0.88 mmol), DMAP (83 mg, 0.68 mmol) and TEA (0.38mL, 2.7 mmol) were added and the reaction stirred overnight. The crudereaction mixture was diluted with DCM (10 mL) and extracted from sat.NH₄Cl (7 mL), dried over MgSO₄, filtered and concentrated. The crudemixture was purified by column chromatography (0% to 5% MeOH in DCM) toafford benzyl4-(2-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methoxy}-2-oxoethyl)piperidine-1-carboxylate10a (270 mg, 0.46 mmol) in a 67% yield.

Step 10B

Benzyl4-(2-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methoxy}-2-oxoethyl)piperidine-1-carboxylate10a (220 mg, 0.37 mmol) was dissolved in DCM (10 mL) and heated to 60°C. Next, Et₃SiH (0.29 mL, 1.86 mmol) was added followed by InBr₃ (394mg, 1.11 mmol) and the reaction was stirred at 60° C. for one hour. Thereaction mixture was concentrated and redissolved in DMF (5 mL),filtered and purified by HPLC to yield4-(2-{[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methoxy}ethyl)piperidine10-1 (m/z 445.5 [MH⁺]).

Table 8 below provides the observed (Obs) ion m/z ratio of the othercompounds that were made according to the procedure as described in thisexample.

TABLE 8

Calc Obs Cpd. —O—R¹ Name mass mass 10-1

4-(2-{[(2R,3S,11bR)-9,10-dimethoxy-3- (2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}ethyl)piperidine 444.34 445.5 10-2

(3R)-3-({[(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}methyl)pyrrolidine 416.3 417.4 10-3

2-[(hexyloxy)methyl]-9,10-dimethoxy-3- (2-methylpropyl)- 417.32 418.41H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinoline 10-4

(2S)-2-({[(2R,3S,11bR)-9,10-dimethoxy- 3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}methyl)pyrrolidine 416.3 417.4 10-5

4-({[(2R,3S,11bR)-9,10-dimethoxy-3-(2- methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}methyl)piperidine 430.32 431.3 10-6

3-({[(2R,3S,11bR)-9,10-dimethoxy-3-(2- yl]methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}methyl)pyrrolidine 416.3 417.4 10-7

(2R)-2-({[(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl]methoxy}methyl)pyrrolidine 416.3 417.4

Example 9 Vmat2 Inhibitor-Induced Reduction of Locomotor Activity

The effect of 1-1 HCl on dopamine depletion was measured using thelocomotor activity (LMA) assay. Following a pre-treatment time 60minutes, male Sprague-Dawley rats (200-250 g) are placed in a clear cagesurrounded by photocell detectors (San Diego Instruments). Rat locomotoractivity is detected by breaks in the photocell beams and activity isdefined as the number of beam breaks in 30 min. Data were analyzed byone-way analysis of variance (ANOVA; SigmaStat version 3.0.1, SPSS,Chicago, Ill.) followed by the Student Newman Keuls post-hoc test forsignificance. The results of this assay are shown in FIG. 1.

Example 10 Conditioned Avoidance Response Assay of AntipsychoticActivity

The conditioned avoidance response (CAR) test has been shown to be aneffective and reliable preclinical model for assessing the antipsychoticactivity of compounds. In the CAR paradigm, a rat is trained in a twochamber shuttle box to respond to a conditioned stimulus (auditory) bynegative reinforcement. If the animal fails to move to the other chamberupon presentation of an auditory stimulus, a mild foot shock is appliedto the side where the rat is located. The rat learns to avoid the mildfoot shock by moving to the other chamber upon initiation of theauditory signal, termed a conditioned avoidance response. Crossing tothe other chamber during administration of the shock is termed an escaperesponse. If a rat fails to move to the other chamber even uponadministration of the foot shock, the rat is considered to have anescape failure. Numerous studies have shown that typical and atypicalantipsychotic drugs selectively suppress CAR, thus making it an idealassay to screen potential antipsychotic compounds (see, e.g., Wadenberget al., Biobehay. Rev. (1999) 23: 851-62).

Male Wistar rats were trained every day for 3 to 4 weeks. In thetraining session, rats were placed in the CAR two-way shuttle box andthe training period of 20 trials ensued. A trial consisted of a 10-secpresentation of an 80 dB white noise followed by a scrambled 0.6 mA footshock lasting up to 20 sec. The inter-trial interval ranged from 20-60sec. The rat learned to avoid shock by moving from one compartment tothe other when the conditioned stimulus was presented (a conditionedavoidance response). A rat was deemed sufficiently trained if it avoidedthe shock when presented with the conditioned stimulus at least 19 timesout of the 20 trials. Rats that did not pass these criteria were notused.

On test day, trained animals were acclimated in the test room for 30minutes prior to testing. They were then dosed with compound 1-1 HCl andplaced in the CAR two-way shuttle box. In the test, 20 trials wereperformed on each rat. In each trial the conditioned stimulus wasapplied (10-sec presentation of 80 dB white noise), followed by the footshock (a scrambled 0.6 mA foot shock lasting up to 20 sec). If theanimal moved to the other chamber on presentation of the conditionedstimulus, it was scored as a conditioned avoidance response. If it movedupon presentation of the foot shock, it was scored as an escape. If itfailed to move upon presentation of the foot shock, it was scored as anescape failure. Antipsychotic efficacy is evident by an increase in thenumber of escapes. Data were analyzed by analysis of variance (ANOVA)followed by post-hoc comparisons with the Bonferroni Test whenappropriate. An effect is considered significant if p<0.05. Outliersdefined as two standard deviations above or below the mean were detectedand were removed from all analysis. Results are shown in FIG. 2 and arereported as mean±SEM for number of escapes.

Example 11 Methods for Determining Vmat2 Inhibitory Activity of aCompound

Examples of techniques for determining the capability of a compound toinhibit VMAT2 are provided below. The procedure is adapted from thatdescribed previously (see, e.g., Near, (1986), Mol. Pharmacol. 30:252-57; Teng, et al., J. Neurochem. 71, 258-65, 1998). Homogenates fromhuman platelets or Sprague-Dawley rat forebrain were prepared byhomogenization and then washed by centrifugation as described previously(see, e.g., Hoare et al., (2003) Peptides 24:1881-97). In a total volumeof 0.2 mL in low-binding 96-well plates (Corning #3605), twelveconcentrations of Compound 1-1 and R,R,R-DHTBZ were competed against 6nM ³H-dihydrotetrabenezine (American Radiolabeled Chemicals, Kd 2.6 nM)on rat forebrain homogenate (100 μg membrane protein per well) or humanplatelet homogenate (50 μg membrane protein per well) in VMAT2 bindingbuffer (Dulbecco's phosphate buffered saline, 1 mM EDTA, pH 7.4).Following incubation at 25° C. for two hours, bound radioligand wascollected by rapid filtration onto GF/B glass fiber filters using aUnifilter-96 Harvester (PerkinElmer). Filter plates were pre-treated for10 minutes with 0.1% polyethylenimine, and following harvesting thefilter plates were washed with 800 μl VMAT2 binding buffer. Boundradioligand was quantified by scintillation counting using a TopcountNXT (PerkinElmer). The results of the competition binding studies arepresented below in Table 9 and Table 10.

TABLE 9 Rat Forebrain VMAT2 Affinity from Competition Binding StudiesCompound pKi (n) Ki (nM) Compound 1-1 8.6 ± 0.1 (2) 2.6 R,R,R-DHTBZ 8.7± 0.2 (6) 1.9

TABLE 10 Human Platelet VMAT2 Affinity from Competition Binding StudiesCompound pKi (n) Ki (nM) Compound 1-1 8.3 ± 0.1 (2) 5.2 R,R,R-DHTBZ 8.6± 0.3 (3) 2.6

The human Ki's for the compounds listed in Table 11 were determinedusing a slightly modified procedure shown below (see data in columnunder the heading “Ki nM”). In a total volume of 0.15 mL in low-binding96-well plates (Corning #3605), twelve concentrations of Compound 1-1and R,R,R-DHTBZ were competed against 10 nM ³H-dihydrotetrabenezine(American Radiolabeled Chemicals, Kd 2.6 nM) on rat forebrain homogenate(100 μg membrane protein per well) or human platelet homogenate (15 μgmembrane protein per well) in VMAT2 binding buffer (Dulbecco's phosphatebuffered saline, 1 mM EDTA, pH 7.4). Following incubation at 25° C. for90 minutes, bound radioligand was collected by rapid filtration ontoGF/B glass fiber filters using a Unifilter-96 Harvester (PerkinElmer).Filter plates were pre-treated with 0.1% polyethylenimine and allowed todry overnight, and following harvesting the filter plates were washedwith 800 μl VMAT2 binding buffer. Bound radioligand was quantified byscintillation counting using a Topcount NXT (PerkinElmer). In Table 11,compounds having a K_(i) of less than 10 nM are identified as “+++”,compounds having a K_(i) of from 10 nM to 500 nM are identitied as “++”,and compounds having a K_(i) greater than 500 nM are identified as “+”(NT=not tested).

TABLE 11 Activity Data for Representative Compounds Human Cpd. No. Ki nM(% max. bioavail.) Rat(% max. bioavail.) 2-1  +++ ++ + 2-2  +++ +++ +++2-3  +++ +++ +++ 2-4  +++ +++ ++ 2-5  +++ +++ ++ 2-6  +++ +++ +++ 2-7 +++ ++ ++ 2-8  +++ +++ ++ 2-9  +++ ++ + 2-10 +++ + ++ 2-11 +++ +++ +++2-12 +++ ++ ++ 2-13 +++ ++ ++ 2-14 +++ +++ ++ 2-15 +++ ++ ++ 2-16 ++++++ +++ 2-17 ++ +++ +++ 2-18 +++ +++ +++ 2-19 +++ NT NT 2-20 NT +++ +++2-21 +++ +++ +++ 2-22 +++ +++ +++ 2-23 +++ +++ +++ 2-24 ++ +++ +++ 2-25+++ NT + 2-26 +++ +++ +++ 2-27 ++ +++ ++ 2-28 ++ +++ +++ 2-29 ++ +++ +++2-30 +++ ++ + 2-31 +++ ++ ++ 2-32 +++ ++ ++ 2-33 ++ NT NT 2-34 +++ ++++++ 2-35 + + + 2-36 +++ ++ ++ 2-37 ++ +++ +++ 2-38 ++ +++ +++ 2-39 ++++++ +++ 3-1  + NT + 3-2  +++ +++ +++ 3-3  ++ + + 3-4  ++ + + 3-5  ++ NTNT 3-6  ++ + + 3-7  ++ + + 3-8  ++ + + 3-9  ++ + + 3-10 + + +++3-11 + + + 3-12 ++ + + 3-13 ++ + + 4-1  +++ + + 4-2  +++ +++ +++ 4-3  +++++ ++ 4-4  +++ ++ ++ 4-5  NT NT NT 4-6  ++ +++ +++ 4-7  +++ + ++ 4-8 +++ + + 4-9  NT NT NT 4-10 +++ + + 4-11 ++ NT NT 4-12 +++ +++ ++ 4-13+++ + NT 4-14 +++ ++ ++ 4-15 +++ + + 4-16 +++ + + 4-17 +++ ++ ++ 4-18 ++++ ++ 4-19 ++ NT NT 4-20 +++ NT NT 4-21 ++ NT NT 4-22 +++ NT + 4-23 +++++ + 4-24 +++ NT NT 4-25 ++ ++ + 4-26 +++ + NT 4-27 +++ +++ ++ 4-28+++ + + 4-29 +++ + + 4-30 ++ NT NT 4-31 +++ + + 4-32 ++ +++ ++ 4-33 ++++ ++ 4-34 +++ NT NT 4-35 +++ NT NT 4-36 +++ + ++ 4-37 +++ ++ ++ 4-38+++ + + 5-1  +++ + + 5-2  NT NT NT 5-3  + + + 5-4  +++ + + 5-5  ++ + +5-6  + + + 5-7  + ++ ++ 5-8  NT NT NT 5-9  + + + 5-10 NT NT + 5-11++ + + 5-12 NT NT NT 5-13 NT NT NT 5-14 + + + 5-15 ++ +++ + 5-16 NT NTNT 5-17 ++ + + 5-18 +++ +++ ++ 5-19 ++ + + 5-20 ++ + + 5-21 +++ ++ +5-22 NT NT NT 5-23 ++ + + 5-24 +++ ++ + 5-25 + + + 5-26 + + + 5-27 + + +5-28 + + + 5-29 ++ ++ ++ 5-30 + + + 5-31 +++ +++ ++ 5-32 +++ + + 5-33 NTNT NT 5-34 ++ + + 5-35 ++ NT NT 5-36 NT NT NT 5-37 +++ ++ ++ 5-38 NT NTNT 5-39 ++ + + 5-40 ++ + + 5-41 ++ + + 5-42 ++ + + 5-43 + + + 5-44 ++++++ ++ 5-45 + NT NT 5-46 + + + 5-47 ++ + + 5-48 +++ +++ +++ 5-49 ++ + NT5-50 +++ +++ ++ 5-51 NT NT NT 5-52 + + + 5-53 ++ ++ ++ 5-54 + + + 5-55NT NT NT 5-56 ++ + + 5-57 + + + 6-1  +++ + + 6-2  +++ ++ + 6-3  NT + +6-4  +++ + + 6-5  +++ + + 6-6  +++ + + 6-7  +++ + + 6-8  ++ + + 6-9  +++++ ++ 6-10 +++ + + 6-11 +++ + + 6-12 NT NT NT 6-13 +++ + + 6-14 +++ ++++ 7-1  ++ +++ +++ 8-1  ++ +++ +++ 9-1  +++ NT NT 9-2  NT NT NT 9-3  +NT NT 9-4  +++ NT NT 9-5  +++ NT NT 9-6  NT NT NT 9-7  NT NT NT 9-8  +++NT NT 9-9  NT NT NT 10-1  +++ NT ++ 10-2  +++ + ++ 10-3  ++ +++ ++ 10-4 +++ +++ +++ 10-5  ++ NT NT 10-6  +++ + ++ 10-7  +++ +++ ++

Another technique that may be routinely performed to determine thecapability of a compound to inhibit VMAT2 is provided below. Thefollowing procedure is adapted from a previously described method (seeTeng, et al., J. Neurochem. 71, 258-65, 1998).

Preparation of rat striatal vesicles: Rat striata from three rats arepooled and homogenized in 0.32 M sucrose. The homogenate is thencentrifuged at 2,000×g for 10 min at 4° C. and the resulting supernatantis centrifuged at 10,000×g for 30 min at 4° C. The resulting pelletcontaining the enriched synaptosomal fraction (2 mL) is subjected toosmotic shock by addition of 7 mL of distilled H₂O, and subsequently thesuspension is homogenized. The osmolarity is restored by the addition of0.9 mL of 0.25 M HEPES and 0.9 mL of 1.0 M neutral L-(+)-tartaric aciddipotassium salt buffer (pH 7.5), followed by a 20 min centrifugation(20,000×g at 4° C.). The supernatant is then centrifuged for 60 min(55,000×g at 4° C.) and the resulting supernatant is centrifuged for 45min (100,000×g at 4° C.). The resulting pellet is resuspended in 25 mMHEPES, 100 mM L-(+)-tartaric acid dipotassium salt, 5 mM MgCl₂, 10 mMNaCl, 0.05 mM EGTA, pH 7.5 to a protein concentration of 1-2 mg/mL andstored at −80° C. for up to 3 weeks without appreciable loss of bindingactivity. Immediately before use, the final pellet is resuspended inbinding buffer (25 mM HEPES, 100 mM L-(+)-tartaric acid dipotassiumsalt, 5 mM MgCl₂, 10 mM NaCl, 0.05 mM EGTA, 0.1 mM EDTA, 1.7 mM ascorbicacid, pH 7.4).

[³H]-dihydrotetrabenazine (DHTBZ) Binding: Aliquots of the vesiclesuspension (0.16 mL, 15 μg of protein/mL) are incubated with competitorcompounds (ranging from 10⁻⁶ to 10⁻¹² M) and 2 nM[³H]-dihydrotetrabenazine (HTBZ; specific activity: 20 Ci/mmol, AmericanRadiolabeled Chemicals, Inc.) for 1 h at room temperature in a totalvolume of 0.5 mL. The reaction is terminated by rapid filtration of thesamples onto Whatman GF/F filters using a Brandel cell harvester.Nonspecific binding is determined using 20 μM tetrabenazine (TBZ).Filters are previously soaked for 2 h with ice-cold polyethyleneimine(0.5%). After the filters are washed three times with the ice-coldbuffer, they are placed into scintillation vials with 10 mLscintillation cocktail. Bound radioactivity is determined byscintillation spectrometry.

Example 12 Methods for Determining Metabolic Pathways of a Compound

To investigate differences in the metabolism of Compound 1-1 andR,R,R-DHTBZ in vitro both compounds were incubated with humanhepatocytes and the amounts of metabolites formed via the respectivedemethylation, oxidation, and glucuronidation pathways were determinedby LC-MS/MS. The instrument responses for all metabolites were assumedto be approximately equal. For both compounds the percentage of overallin vitro metabolism due to the respective pathways (fractionmetabolized, fm) was calculated by dividing the LC/MS peak area of themetabolite(s) formed via a given pathway by the sum of the peak areas ofall metabolites monitored. Results of this analysis indicated thatR,R,R-DHTBZ was primarily metabolized by demethylation. Thisdemethylation is believed to be catalyzed by CYP2D6. In contrast,Compound 1-1 was primarily metabolized by glucuronidation. FIG. 3illustrates the contribution of metabolic pathways to the overall invitro metabolism of Compound 1-1 and R,R,R-DHTBZ using humanhepatocytes.

Example 13 Method to Determine Stability of Compounds in Mammalian LiverMicrosomes

Test compound (1 uM) was incubated with pooled mixed gender livermicrosomes from humans (0.5 mg/mL total protein) and SD rats (0.1 mg/mLtotal protein) at 37° C. in the presence of an NADPH-generating systemcontaining 50 mM, pH 7.4 potassium phosphate buffer, 3 mM magnesiumchloride, 1 mM EDTA, 1 mM NADP, 5 mM glucose-6-phosphate, and 1 Unit/mLglucose-6-phosphate dehydrogenase. All concentrations were relative tothe final incubation volume of 250 uL. Incubations were conducted at 37°C. for 0, 5, 10, 20, 40 and 60 minutes in a water bath and terminated byrapid mixing with 300 uL of ice-cold acetonitrile containing 0.1% formicacid. Internal standard was added and proteins were precipitated andremoved by centrifugation prior to LC/MS analysis. Aliquots of theresulting supernatant fractions were analyzed by LC/MS monitoring fordepletion of parent compound. The resultant peak area ratio versus timedata was fitted to a non-linear regression using XLfit Scientific CurveFitting Software (IDBS Ltd., Surrey, UK) and half-life was calculatedfrom the slope. Pharmacokinetic parameters were predicted using themethod described by Obach et al (J. Pharmcol. Exp. Ther. 1997; 283:46.58). Briefly, values for intrinsic clearance were calculated from thein vitro half-life data and were then scaled to represent the clearanceexpected in the entire animal (human or rat). Additional valuescalculated included predicted extraction ratio and predicted maximumbioavailability.

By the above procedures, the predicted maximum bioavailability (humanand rat) for the compounds listed in Table 11 above were calculated (seedata in columns under the headings “Human (% max. bioavail.)” “Rat (%max. bioavail.)”, respectively). In Table 11, compounds having apredicted maximum bioavailability of less than 10% are identified as“+++”, compounds having a predicted maximum bioavailability from 10% to50% are identitied as “++”, and compounds having a predicted maximumbioavailability of greater than 50% to 100% are identified as “+”(NT=not tested).

Example 14 Method to Determine Hydrolytic Stability of Compounds inMammalian Intestinal S9

Compounds that demonstrated metabolic stability in the human livermicrosomal screening assay, defined as scaled intrinsic clearance of <20mL/min/kg (approximately >50% predicted bioavailability), were selectedfor further evaluation of hydrolytic stability in an in vitro intestinalS9 assay (SD rat and human). Compounds (1 uM) were incubated with pooledintestinal S9 subcellular preparations (0.5 mg/mL total protein) from SDrats and humans without the addition of protease inhibitorphenylmethylsulfonylflouride. Incubations were carried out in apotassium phosphate buffer (50 mM). All concentrations were relative tothe final incubation volume of 125 uL. Incubations were conducted at 37°C. for 0, 5, 10, 20, 40 and 60 minutes in a water bath and terminated byrapid mixing with 150 uL of ice-cold acetonitrile containing 1% formicacid. Internal standard was added and proteins were precipitated andremoved by centrifugation prior to LC/MS analysis. Aliquots of theresulting supernatant fractions were analyzed by LC/MS monitoring fordepletion of the test compound and formation of compound 1-1. Theresults were used to categorize compounds based on their potential tohydrolyze to form compound 1-1 in the in vitro assay.

The results of this assay are presented in Table 12. To this end, thecompounds listed in Table 12 were separated into three classes ofcompounds based on their ability to form compound 1-1: high (identifiedas “+++”); moderate (identitied as “++”), and low (identified as “+”).

TABLE 12 Activity Data for in vitro Human Intestinal S9 Hydrolysis AssayCompound S9 Assay 2-10 +++ 2-25 +++ 3-1  + 3-3  +++ 3-4  ++ 3-6  ++3-7  + 3-8  +++ 3-9  ++ 3-10 +++ 3-11 ++ 3-12 +++ 3-13 ++ 4-1  ++ 4-7 ++ 4-8  ++ 4-10 ++ 4-13 +++ 4-15 + 4-16 + 4-22 ++ 4-26 ++ 4-28 ++ 4-29+++ 4-31 ++ 4-36 +++ 4-38 + 5-1  + 5-3  + 5-4  + 5-5  + 5-6  + 5-9  +5-11 ++ 5-14 + 5-17 + 5-19 + 5-20 ++ 5-23 ++ 5-25 + 5-26 + 5-27 + 5-28 +5-30 + 5-32 ++ 5-34 + 5-39 +++ 5-40 + 5-41 + 5-42 ++ 5-43 + 5-46 ++5-47 + 5-49 + 5-52 + 5-54 + 5-56 + 5-57 + 6-1  + 6-3  + 6-4  + 6-5  ++6-6  + 6-7  + 6-8  + 6-10 + 6-11 + 6-13 +

The various embodiments described above can be combined to providefurther embodiments. All U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications, and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet areincorporated herein by reference in their entirety. Aspects of theembodiments can be modified, if necessary to employ concepts of thevarious patents, applications and publications to provide yet furtherembodiments.

These and other changes can be made to the embodiments in light of theabove-detailed description. In general, in the following claims, theterms used should not be construed to limit the claims to the specificembodiments disclosed in the specification and the claims, but should beconstrued to include all possible embodiments along with the full scopeof equivalents to which such claims are entitled. Accordingly, theclaims are not limited by the disclosure.

1. A compound having structure (I):

or a stereoisomer or pharmaceutically acceptable salt or solvatethereof, wherein: R¹ is b) —P(═O)(OR³)₂; c) —C(═O)alkyl, wherein alkylis optionally substituted with R¹⁰ and/or R²⁰; d) —C(═O)heterocyclyl,wherein heterocyclyl is optionally substituted with R¹⁰ and/or R²⁰; e)—C(═O)carbocyclyl, wherein carbocyclyl is optionally substituted withR¹⁰ and/or R²⁰; f) —C(═O)N(R₃)alkyl, wherein alkyl is optionallysubstituted with R¹⁰ and/or R²⁰; g) —C(═O)N(R₃)carbocyclyl, whereincarbocyclyl is optionally substituted with R¹⁰ and/or R²⁰; h)—C(═O)Oalkyl, wherein alkyl is optionally substituted with R¹⁰ and/orR²⁰; or i) alkyl, wherein alkyl is optionally substituted with R¹⁰and/or R²⁰; and wherein, each R³ is independently hydrogen or alkyl;each R¹⁰ is independently halo, haloalkyl, cyano, nitro,trimethylsilanyl, —OR³⁰, —SR³⁰, —OC(O)—R³⁰, —N(R³⁰)₂, —C(O)R³⁰,—C(O)OR³⁰, —C(O)N(R³⁰)₂, —N(R³⁰)C(O)OR³¹, —N(R³⁰)C(O)R³¹,—N(R³⁰)C(═NR³¹)N(R³²)₂, —N(R³⁰)S(O)_(t)R³¹ (where t is 1 to 2),—S(O)_(t)OR³⁰ (where t is 1 to 2), —S(O)_(p)R³⁰ (where p is 0 to 2) or—S(O)_(t)N(R³⁰)₂ (where t is 1 to 2), —OP(═O)(OR³⁰)₂, or when a singleatom bears two R¹⁰ groups such two R¹⁰ groups may be taken together toform oxo; each R²⁰ is independently alkyl, alkenyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclalkyl, heteroarylor heteroarylalkyl, or when a single atom bears two R²⁰ groups such twoR²⁰ groups may be taken together to form cycloalkyl, wherein each ofsaid alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclalkyl, heteroaryl and heteroarylalkyl groups isoptionally substituted with R¹⁰ and/or R²²; each R²² is independentlyalkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclalkyl, heteroaryl or heteroarylalkyl, whereineach of said alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclalkyl, heteroaryl and heteroarylalkyl groups isoptionally substituted with R¹⁰; and each R³⁰, R³¹ and R³² isindependently hydrogen or alkyl. 2-3. (canceled)
 4. The compound ofclaim 1, wherein R¹ is —P(═O)(OR₃)₂.
 5. The compound of claim 1, whereinR¹ is —C(═O)alkyl, and wherein alkyl is optionally substituted with R¹⁰and/or R²⁰.
 6. The compound of claim 5, wherein the compound is selectedfrom one of the following:

Cpd. O—R¹ 2-1

2-2

2-3

2-4

2-5

2-7

2-8

2-9

2-10

2-13

2-14

2-15

2-16

2-17

2-19

2-23

2-24

2-28

2-29

2-30

2-32

2-33

2-34

2-35

2-36

2-39

3-1

3-2

3-3

3-7

3-8

3-9

3-10

3-11

3-12

3-13

4-2

4-9

4-10

4-12

4-14

4-16

4-17

4-19

4-23

4-24

4-28

4-30

4-31

4-33

4-34

4-36

4-37

4-38


7. The compound of claim 1, wherein R¹ is —C(═O)heterocyclyl, andwherein heterocyclyl is optionally substituted with R¹⁰ and/or R²⁰. 8.The compound of claim 7, wherein the compound is selected from one ofthe following:

Cpd. O—R¹ 2-6

2-11

2-12

2-18

2-21

2-22

2-25

2-26

2-27

2-31

2-37

4-1

4-3

4-4

4-5

4-6

4-7

4-8

4-11

4-13

4-15

4-20

4-21

4-22

4-26

4-27

4-29

4-32

4-35

5-4

5-6

5-7

5-8

5-12

5-13

5-14

5-15

5-18

5-21

5-24

5-27

5-31

5-37

5-43

5-44

5-48

5-49

5-50

5-52

5-53

5-54

6-1

6-2

6-3

6-4

6-5

6-6

6-7

6-8

6-9

6-10

6-11

6-12

6-13

6-14


9. The compound of claim 1, wherein R¹ is —C(═O)carbocyclyl, and whereincarbocyclyl is optionally substituted with R¹⁰ and/or R²⁰.
 10. Thecompound of claim 9, wherein the compound is selected from one of thefollowing:

Cpd. O—R¹ 2-20

2-38

3-4

3-5

3-6

4-18

4-25


11. The compound of claim 1, wherein R¹—C(═O)N(R₃)alkyl, and whereinalkyl is optionally substituted with R¹⁰ and/or R²⁰.
 12. The compound ofclaim 11, wherein the compound is selected from one of the following:

Cpd. O—R¹ 5-1

5-2

5-3

5-5

5-10

5-11

5-16

5-17

5-19

5-20

5-22

5-23

5-25

5-26

5-28

5-29

5-30

5-32

5-33

5-34

5-36

5-38

5-39

5-42

5-45

5-46

5-47

5-51

5-55

5-56

5-57


13. The compound of claim 1, wherein R¹ is —C(═O)N(R₃)carbocycle, andwherein carbocycle is optionally substituted with R¹⁰ and/or R²⁰. 14.The compound of claim 13, wherein the compound is selected from one ofthe following:

Cpd. O—R¹ 5-9

E 5-35

E 5-40

E 5-41

E


15. The compound of claim 1, wherein R¹—C(═O)Oalkyl, and wherein alkylis optionally substituted with R¹⁰ and/or R²⁰.
 16. The compound of claim15, wherein the compound is:

Cpd O—R¹ 8-1


17. The compound of claim 1, wherein —R¹ is alkyl, and wherein alkyl isoptionally substituted with R¹⁰ and/or R²⁰.
 18. The compound of claim17, wherein the compound is:

Cpd. O—R¹ 9-1

9-2

9-3

9-4

9-5

9-6

9-7

9-8

9-9

10-1

10-2

10-3

10-4

10-5

10-6

10-7


19. The compound of claim 1 having the following stereochemistry:


20. A pharmaceutical composition comprising a compound of claim 1 incombination with a pharmaceutically acceptable excipient and/or diluent.21. A method of treating a hyperkinetic disorder comprisingadministering to a subject in need thereof a pharmaceutically effectiveamount of a compound of claim
 1. 22. The method of claim 21, wherein thehyperkinetic disorder is Huntington's disease, tardive dyskinesia,Tourette's syndrome or tics.